Submicron aqueous aerosols containing lecithin

ABSTRACT

AEROSOLS OF AQUEOUS PARTICLES OF SUBMICRON DIAMETER WHICH ARE STABLE AGAINST EVAPORATION AND SUITABLE TO BE READILY TRANSMITTED TO THE ALVEOLI OF THE LUNG BY INSPIRATION, MAY BE PREPARED FROM AQUEOUS LECITHIN DISPERSIONS NEBULIZED, AS BY AN ULTRASONIC NEBULIZER, AT TEMPERATURES GREATER THAN ABOUT 25*C. LECITHIN AEROSOLS THUS PREPARED ARE USEFUL FOR THE TREATMENT OF LUNG DISORDERS, AND MAY OPTIONALLY CONTAIN OTHER THERAPEUTIC AGENTS SUCH AS ANTIOBIOTICS.

United States Patent Oflice 3,594,476 Patented July 20, 1971 3,594,476SUBMICRON AQUEOUS AEROSOLS CONTAINING LECITHIN Edward W. Merrill,Cambridge, Mass, assignor to Massachusetts Institute of Technology,Cambridge, Mass. No Drawing. Filed May 12, 1969, Ser. No. 823,972 Int.Cl. A61 3/02; A61k 13/00 US. Cl. 424-199 4 Claims ABSTRACT OF THEDISCLOSURE Aerosols of aqueous particles of submicron diameter which arestable against evaporation and suitable to be readily transmitted to thealveoli of the lung by inspiration, may be prepared from aqueouslecithin dispersions nebulized, as by an ultrasonic nebulizer, attemperatures greater than about 25 C. Lecithin aerosols thus preparedare useful for the treatment of lung disorders, and may optionallycontain other therapeutic agents such as antibiotics.

This invention relates to the preparation of aqueous aerosols, and inparticular to aqueous aerosols containing lecithin of sufficiently smallparticle size to be inspired into the alveoli of the lung.

Many efforts have been made to prepare aqueous aerosols of sub micronparticle size small enough to be inhaled into the alveoli of the lung,and also to prepare aerosols containing lecithin which is known to beuseful in the treatment of various lung disorders.

Aqueous aerosols of extremenly small particle size, e.g., less than onemicron, are characterized by extreme instability because of the veryrapid rate at which particles of this size evaporate in favor of thegrowth of particles of much larger diameter. As a consequence there hasnot been any reliable means for preparing aqueous aerosols of such smallparticle size. Prior attempts to prepare aerosols containing lecithinhave utilized Freon type gasses, themselves toxic, or have made use ofmixtures of water and glycol type compounds of low vapor pressure thatavoid the evaporation problem.

I have now discovered that aqueous, or essentially aqueous, aerosols canbe prepared by dispersing lecithin in water, and then nebulizing thedispersion at a temperature in excess of about 25 C. It appears that atabout 25 C. DL dipalmitoyl-u-lecithin undergoes a transformation,evidenced, inter alia, 'by a marked decrease 1n its surface viscosity,the effect of which is to permit the formation of staple aqueousparticles of less than one micron diameter.

Aerosols thus prepared are of particle size generally between 0.2 and 1micron in diameter and have been shown to be useful in the treatment ofrespiratory distress syndrome and hyaline membrane disease, for whichlecithin is known to be therapeutic. Robillard, J. E., et al. AerosolAdministration of Synthetic 18, Dipalmitoyl-L- a-Lecithin in theRespiratory Distress Syndrome: A Preliminary Report, Canad. Med. Ass.1., Jan. 11, 1964, vol. 90, pp. 55 if. By the use of this invention aconvenient and effective means of carrying the lecithin into the alveoliof the lungs is provided.

In addition aerosols prepared pursuant to this invention may be utilizedas carriers for therapeutic and diagnostic reageants or otherme'dicants.

In preparing a solution for 'aerosolization (nebulization) it is onlynecessary to suspend between 100 milligrams and grams of the DLdipalmitoyl-u-lecithin in 100 ml. of water, or preferably an isotonicsaline solution, and dissolving in the solution any desired othermedicant or reagent. Prior to nebulization the solution should he heatedto at least about 25 C. (but preferably to not more than C.) and thensubjected to nebulization by conventional means. An ultrasonic nebulizeroperating at about 800,000 Hz. at 15 watts energy is sufficient. Asuitable device is the Ultramist III which is marketed by MacronsonicsCorp. 88 Elston Street, Rahway, N. J. 07065.

It is interesting to note in passing that the literature pertaining tothe Ultramist III states that traces of surface-active agents (soap, forinstance) considerably alter the mechanism of ultrasonic fogging at theair/liquid interface and may even suppress it completely.

The following example sets forth a preferred procedure for practicingthe invention.

Two grams of DL-dipalmitoyl-a-lecithin are dispersed in 100 millilitersof a 0.15M aqueous sodium chloride solution using a sonic cavitationgenerator (Branson Heat Systems Sonifier Wl= D, 20 kHz.). Afterdispersion the solution containing the lecithin is heated to atemperature greater than about 25 (3., preferably to about 37 C. whenthe aerosol is to be administered to human beings, and is thenaerosolized in an ultrasonic generator, such as the Ultramist III,previously identified. In the operation of the ultrasonic generator acarrier air stream is supplied to carry away the aerosol and it ispreferred that this also be heated to about 37 C. The rate of air flowshould be adjusted to between 1 and 12 inches per second. (%9 cu.in./sec.)

A description of the ultrasonic generator and its operation is containedin Boucher, R. M. G., and J. Kreuter, The Fundamentals of the UltrasonicAtomization of Medicated Solutions, Annals of Allergy, Volume 26,November 1968, page 591 ff.

In general it will be noted that the suspensions from which the aerosolsare produced according to this invention contain water as the principalvolumetric component, and lecithin as the principal surface activeagent. In addition to the DL dipalmitoyl-tx-lecithin, it is contemplatedthat others may be used which contain, per molecule, two residues fromother acids such as palmitic stearic, or oleic, these being adjacent onthe beta and gamma carbons of the glycerol unit, with thephosphatidylcholine on the alpha carbon. The acyl residues may be ofeither the D, L or DL racemic configurations.

Aerosols described above prepared from a two weight percent DLdipalmitoyl-a-lecithin suspension in saline in air saturated with watervapor at 37 C. have been found to have particle sizes ranging from 0.2to approximately 1.2 microns. By contrast a controlled saline generatedunder the same conditions, but without lecithin suspended thereinproduces particles larger by a factor of 10, as estimated by Stokesiansettling velocity.

The lecithin added to water must be dispersed to a colloidal or micellarstate of suspension in water by any nondestructive means, of whichexposure to ultrasonicly induced cavitation is the most expedient. Inaddition to the dispersed lecithin, the suspension to be aerosolized maycontain cationic components such as sodium, potas sium, calcium, andother metal ions, anionic components such as bicarbonate, chloride,sulfate and phosphate ions, non electrolytes such as glucose and othersaccharides, and specific chemotherapeutic agents such as pencillin,streptomycin and other antibiotics, radioactive isotopes such as cobalt,strontium, calcium, either in colloidal suspension or in true solution,provided that the total molarity of all the solutes, exclusive of thelecithin, be not more than 2 molal. Colloidal materials other thanlecithin must be dispersible into particles having dimensionssubstantially less than 1000 A.

Water soluble medicants, such as penicillin, streptomycin, ammoniumchloride and organic and inorganic radioisotopes do not significantlyalter the requirement for the minimum temperature of about 25 C. Incontrast, lipid soluble medicants, fluorocarbons, chlorinatedhydrocarbons, and most proteins alter the minimum temperature for theaerosolization in an indeterminant way, but the temperature may bedetermined by routine experimentation.

Although this invention has been described with specific reference toits preferred embodiment it is contemplated that obvious modificationswill occur to those skilled in the art and familiar with the principlesherein set forth and that such modifications may be made withoutdeparting from the scope of this invention. Specially it is contemplatedthat where the aerosol is to be formed for human administration that thedispersion will be formed under sterile conditions.

Having thus disclosed my invention and described in detail the preferredembodiment thereof, I claim and desire to secure by Letters Patent:

1. The method of preparing an essentially aqueous lecithin aerosolstable against evaporative growth to larger diameter particles, whichcomprises the steps of dispersing D,L dipalmitoyl-a-lecithin in anessentially aqueous medium in the amount of between about 100 milligramsand 5 grams of lecithin to 100 milliliters of said medium,

bringing the dispersion to a temperature greater than about 25 C. andforming an aerosol by generating aerosol particles between 0.2 andapproximately 1.2 micron in diameter therefrom.

2. The method defined by claim 1 wherein the aerosol is formed in acarrier gas stream.

3. An aerosol composition, stable against evaporative growth, producedin accordance with claim 1, comprising D,L dipalmitoyl-a-lecithindispersed in an essentially aqueous sterile medium in an amount betweenabout 100 milligrams and 5 grams of lecithin to 100 milliliters of saidmedium.

4. The composition defined by claim 3 wherein the medium is an aqueousisotonic saline solution.

References Cited UNITED STATES PATENTS 1,988,050 11/1935 Rosenbusch eta1. 424199 3,038,816 6/1962 Drell et a1 424-199UX 3,056,728 10/1962Ohtaki 424199X OTHER REFERENCES Chem. Abstracts 55: p. 20340h (1961).

SHEP K. ROSE, Primary Examiner US. Cl. X.R.

